L20 Hormonal drug delivery Flashcards
Why do we have dosage forms
- Drug often in powder form
- Tiny doses of drug (mg or mcg quantities)
- Bulk up with excipients (such as water, lactose)
Why do we have different dosage forms?
- Different clinical conditions
- Different types of patient
- Different routes of administration
- Different physicochemical properties of drug
Factors to consider when designing dosage forms
- Drug factors (solubility, partition coefficient, pKa, stability, MWt)
- Biopharmaceutical factors (absorption, bioavailability, route of administration)
- Therapeutic factors - disease, patient, route, local vs systemic delivery
Types of hormones
- Modified amino acid derivatives
- Peptide and proteins
- Steroids
- Eicosanoids
What are modified amino acid derivatives derived from
- Derived from tyrosine and tryptophan
Examples of modified amino acid derivatives
- Dopamine, thyroxine
What are peptides and proteins derived from
- Derived from amino acids
Examples of peptides and proteins
- Neuropeptides (vasopressin), pituitary hormones(gonadotropins), GI hormones (insulin)
What are steroids derived from
- Cholesterol
Examples of steroids
- Sex hormones (testosterone)
- Corticosteroids (hydrocortisone)
What are eicosanoids derived from
- Derived from lipids
Examples of eicosanoids
- Prostaglandins, leukotrienes
Main feature of modified amino acid derivatives
- Generally orally active
Main features of peptide and proteins
- Vary considerably in size from 3 amino acids to large, multisubunits glycoproteins
- Susceptible to enzymatic degradation in GIT
- Low absorption
Main features of steroids
eg. sex hormones
- Variable absorption
- Susceptible to extensive first pass hepatic metabolism
- Orally active BUT systemic Side effects
Give examples of when you might not want systemic delivery of a drug
Might not want systemic delivery of a drug if:
- Side effects eg. corticosteroids
- Bioavailability is low eg. peptide hormones, sex hormones
Examples of excipients
- Diluents/fillers eg. lactose, water
- Surfactants eg. polysorbates
- Lubricants eg. Mg sterate
- Disintegrants eg. starch
- Viscosity enhancing agents eg cellulose derivatives
- Flavours, colours, perfumes
- Sweetening agents
- Preservatives
Features of local delivery
- Site of administration = site of action
- Rapid onset of action
- Less drug required
- Absorption into the blood stream is not required
- Absorption into the blood stream can lead to unwanted side effects
Why might corticosteroids be administered locally via different dosage forms
To avoid systemic side effects, need many different dosage forms
Intra-articular injections cortisone - tennis elbow
Creams and ointments betamethasone - eczema
Inhalers e.g. beclomethasone for asthma
Eye drops dexamethasone for inflammatory conditions of eye
Suppositories hydrocortisone inflammatory conditions of rectum
Factors to consider when administering modified amino acid derivatives and corticosteroids
Drug factors - low dose required
Biopharmaceutical factors - which route? orally bioavailable
Therapeutic factors - local vs systemic delivery
Factors to consider when administering peptide hormones eg insulin
Drug factors - peptide hormone, large molecule MW - 5800 Da
Biopharmaceutical factors - not absorbed after oral administration
Therapeutic factors - need systemic action, aim to mimic insulin secretion by normal pancreas - basal and bolus
Why are peptide hormones not absorbed after oral administration
- Not absorbed after oral administration because of enzymatic degradation in lumen of GIT
- Any that survives can’t readily cross GI epithelium into blood because too large
How are insulins characterised
Insulins characterised by differences in:
Onset - how quickly they act
Peak - how quickly they achieve max impact
Duration - how long they last
Route of delivery - subcutaneous, inhaled
When are rapid-acting insulins used
- Rapid-acting insulins are used in insulin pumps, also known as continuous subcutaneous insulin infusion (CSII) devices
- When delivered through a CSII pump, the rapid-acting insulins provide the basal insulin replacement, as well as the mealtime and high blood sugar correction insulin replacement
Advantages of pulmonary route - systemic delivery
- Large surface area (80-140 m2)
- Thin epithelial barrier (0.1-0.2 um)
- Good blood supply (100% cardiac output)
- Avoids harsh environment of GI tract
- Avoids first-pass hepatic metabolism
When is rapid-acting inhaled insulin taken
- Taken at the beginning of each meal
What is inhaled insulin taken in combination
- Used in combination with a long-acting injected insulin
Factors to consider when administering sex hormones
Drug factors - steroid, lipophilic, MW - 270 Da
Biopharmaceutical factors - variable absorption after oral administration, extensive first pass hepatic metabolism, short t1/2
Therapeutic factors - systemic delivery required but try to avoid oral route. Either cyclical or continuous administration required
Why do we need alternatives to oral route of administration
- To increase bioavailability
- To offer sustained release
Alternative routes of administration to the oral route
- Parenteral route - IM injection, implant
- Transdermal route - patch or gel
- Intranasal route - spray
- Buccal route - mucoadhesive system
- Vagina - gel
Features of IM injections
Oily injections - sustained release
- Testosterone enantate (caster oil)
- Testosterone decanoate, isocaprate, phenylproprionate and proprionate, undecanoate
Implants - sustained release
- Nexplanon (progestogen-nly contraception)
Features of oily injections - IM injection
- Sustained action because of lower rate of partition from oily vehicle into aqueous environment of tissue
- Ester form of testosterone - DEPOT preparation - every 2-3 weeks
- Requires esterases at injection site to cleave active drug from ‘pro’ drug
Effects of ester at position 17
- Decreases water solubility
- Increases oil solubility
- Deactivates molecule - can’t bind to androgen receptor
- Ester cleaved/hydrolysed in blood - restores-OH so can attach to receptor
How does release of steroid molecules from oily depots of long-chain esters in muscle tissue occur
- Oil has some affinity for water and thus allows penetration of water; the ester is hydrolysed at the surface of the droplet
Effect of total surface area of the droplet on the pharmokinetics of the drug
- The total surface area of the droplet can influence release rate and hence pharmokinetics of the drug
Droplet dimenions and total surface area influenced by:
force of injection
viscosity and surface tension of oil phase
size of needle
environment into which it’s injected – exercise can increase plasma levels by increasing surface area of droplet.
What is an etonogestrel(nexplanon) implant
The etonogestrel implant is a single-rod progestin contraceptive placed subdermally in the inner upper arm for long-acting reversible contraception in women
How is etonogestrel implant delivered
- Sub dermal implantation
- Provides effective contraception for up to 3 years unless BMI greater than 35 kg/m2 in which case, may not provide effective contraception in 3rd year
Advantages of intranasal administration - systemic
- Large surface area (-180cm2)
- Highly vascularised
- Avoids first pass hepatic metabolism
- Good bioavailability for low MW compounds
Product on the market - desmopressin
Disadvantages of intranasal administration - systemic
- Mucociliary clearance
- Metabolic activity
- Poor bioavailability for high MW compounds
Features of buccal administration - systemic
Mucoadhesive testosterone buccal delivery system:
- Applied twice daily
- Adheres to gum or inner cheek
- Sustained release of testosterone through buccal mucosa
- Eating, tooth brushing, mouthwashing, chewing gum and alcoholic beverages have no significant effect on use and absorption from device
How does the mucoadhesive testosterone buccal delivery system work
- When applied the device begins to hydrate and testosterone is absorbed through the gum and inner cheek surfaces that are in contact with it.
- Venous drainage from mouth is to superior vena cava, therefore avoids first-pass hepatic metabolism.
Physiologic levels of testosterone
300 - 1050 ng/dL
Changes in serum testosterone levels after buccal administration - systemic
- Following initial application, serum testosterone rises to a max within 10-12 hours
- Steady state levels are usually obtained after first two systems are applied
- When removed and not reapplied, serum testosterone levels fall to below normal range in 2-4 hours
Features of vaginal administration - systemic
- Self-insertion and removal
- Continuous release
- Good patient compliance
Bioadhesive vaginal gel (crinone) progesterone released over 25-50 h
What is crinone
- Micronised progesterone and polymer polycarbophil in an oil in water emulsion system
- Polymer, which is insoluble in water, swells within the vagina and forms a bioadhesive gel coating on the walls of the vagina. This allows progesterone to be absorbed through the vaginal tissue over 25 – 50 hours.
Product used to assist reproduction.
Vaginal administration (local) - device
- Vaginal ring (estring)
- Estradiol released over 90 days
What is an estring used for
- Treatment of urogenital symptoms associated with postmenopausal atrophy of the vagina
Example of vaginal administration (local) - pessary
- Estradiol 10 mcg vaginal tablets (inserts) (vagifem)
What is mirena
- intrauterine device (IUD) with progestogen, sold under the brand name Mirena among others, is a intrauterine device that releases the hormone levonorgestrel
What type of contraception does progestasert (mirena) provide
- Progestasert (mirena) provides local rather than systemic contraception
- May inhibit sperm survival and/or alter uterine environment to prevent nidation
Advantages of mirena
- Uses natural hormone at much lower dose than by other routes
- Don’t need to take/admin daily
- No estrogens
- T-shaped device for comfort, safety and retention - minimal mechanically - induce irritation
- Hormonal action confined to uterus
Eicosanoid hormones
- Prostaglandin E2 (prostin E2, dinoprostone)
- Vaginal gel
- Vaginal pessary/tablet (propess)
Duration of PGE2 release
- PGE2 released over 12 hours, local action to ripen cervix
What is PGE2 indicated for
- Indicated for the initiation and/or continuation of cervical ripening at or near term when need to induce birth.
